Imidazo1,5!pyridine derivatives are known, for instance 3-amino-6,7,8,8a-tetrahydro-8a-hydroxyimidazo1,5a!pyridin-1(5H)-one is described by Klein et al. (Liebigs Ann. Chem. 1623-1637, 1983). No pharmacological activity is disclosed for this compound.
The 8-substituted 3,8-diamino-imidazo1,5a!pyridin-1(5H)-one derivatives of the present invention are novel compounds which are selective reversible inhibitors of serine proteases that require a basic amino acid residue at the P.sub.1 position of their substrates.
The invention relates to imidazol1,5a!pyridine derived serine protease inhibitors comprising a unit having the general formula I ##STR2## wherein R.sub.1 is hydrogen, lower alkyl or an acyl group; R.sub.2 is hydrogen or lower alkyl; R.sub.3 and R.sub.4 are independently hydrogen, lower alkyl or together form .dbd.CH--NR.sub.5 R.sub.6, R.sub.5 and R.sub.6 being lower alkyl; or a pharmaceutically acceptable salt thereof.
In the definition of the compounds of formula I the term lower alkyl means a branched or unbranched alkyl group having preferably 1-6 carbon atoms, like hexyl, isobutyl, propyl, isopropyl, ethyl, and, most preferred, methyl.
The term acyl group means a 1-oxoalkyl group derived from carboxylic acid having from 1 to 6 carbon atoms, like hexanoyl, tert-butanoyl, propionyl, acetyl and formyl. The preferred acyl group is the acetyl group.
The serine proteases are a class of proteolytic enzymes that catalyze the hydrolysis of specific peptide bonds in proteinaceous substrates. Schechter and Berger (Biochem. Biophys. Res. Commun. 27, 157-162, 1967) have proposed a now often used nomenclature for the identification of amino acid residues in the substrates of the serine proteases:
Substrate: .about.=scissile bond PA1 . . P.sub.n . . . P.sub.4 -P.sub.3 -P.sub.2 -P.sub.1 .about.P.sub.1 '-P.sub.2 '-P.sub.3 '-P.sub.4 ' . . . P.sub.n ' . . . PA1 Enzyme: PA1 . . S.sub.n . . . S.sub.4 -S.sub.3 -S.sub.2 -S.sub.1 -S.sub.1 '-S.sub.2 '-S.sub.3 '-S.sub.4 ' . . . S.sub.n ' . . .
The amino acid residues of the subsites of the substrate at the N-terminus of the scissile P.sub.1 -P.sub.1 ' bond are designated P.sub.1, P.sub.2 etc. and as P.sub.1 ', P.sub.2 ' etc. at the C-terminus. These subsites of the substrate correspond to the possible subsites (S.sub.1, S.sub.2, etc) on the enzyme with which the binding interactions take place.
The compounds of the present invention are inhibitors of the serine proteases that require a basic amino acid residue, like arginine or lysine, at the P.sub.1 position of their substrates. Representative examples of these serine proteases are trypsin, piasmin, urokinase plasminogen activator, kallikreins, calpain, acrosin, and thrombin.
The present invention provides analogues of peptide substrates, which encompass residues from the P-region of substrates of the pertinent proteases only, in which the terminal P.sub.1 -residue is replaced by the 3,8-diamino-imidazo1,5a!pyridin-1(5H)-one unit of formula I.
It is a major goal of the present invention to provide selective inhibitors of certain serine proteases that form part of the blood clotting cascade. In this enzymatic cascade the activated form of one clotting factor catalyzes the activation of the next factor, ultimately leading to the rapid generation of the arginine-directed (P.sub.1 substrate residue is an arginine) serine protease thrombin (factor IIa) from its precursor prothrombin (factor II). The latter process is catalyzed by factor Xa, which is also an arginine-directed serine protease. Thrombin, the last enzyme in the coagulation system, will cleave the soluble plasma protein fibrinogen to generate fibrin monomers, which are cross-linked to form an insoluble gel. Apart from being involved in the regulation of its own production and activity, thrombin is a potent platelet agonist, thereby inducing platelet aggregation. Activated platelets form together with the fibrin polymer matrix and entrapped erythrocytes the blood clot or thrombus.
Thrombin plays a key role in the process of haemostasis, the physiological process which arrests bleeding from an injured blood vessel. It also plays a role in thrombosis, which is the pathological condition whereby inappropriate activity of the haemnostatic mechanism results in the formation of intravascular thrombi, which in turn lead to interruption of blood flow. Thrombosis can occur in both arteries and veins.
To date two types of anticoagulants, i.e. hepazins and vitamin K antagonists, are in clinical use to prevent thrombosis. Both act indirectly by reducing the activity of thrombin. Heparin mainly acts by accelerating the inactivation of thrombin by its physiological inhibitors like antithrombin III and heparin cofactor II. Heparin only acts when given parenterally. The vitamin K antagonists, of which the coumarin derivative warfarin is a well-known example, are orally active and act by inhibiting the production in functional form of a number of vitamin K dependent coagulation factors (II, VII, IX and X). Because of their mechanism of action these latter agents have a slow onset and reversal of action. Major clinical problems associated with the use of heparins and coumarins are bleeding and their small and unpredictable therapeutic safety margin.
There is a need therefore to develop improved coagulation inhibitors, which for instance inhibit thrombin or factor Xa directly.